Methods and compositions using cetirizine in combination with leukotriene inhibitors or decongestants

ABSTRACT

Methods and pharmaceutical compositions employing (+) cetirizine, (−) cetirizine, or racemic cetirizine, or a pharmaceutically acceptable salt thereof, and a leukotriene inhibitor, or a pharmaceutically acceptable salt thereof, or decongestant for the treatment, management, and/or prevention of inflammation, asthma or symptoms thereof, allergic disorders such as allergic rhinitis, and dermatitis.

1 FIELD OF THE INVENTION

The invention relates to methods of prevention and treatment using, andpharmaceutical compositions containing, cetirizine and a leukotrieneinhibitor.

2 BACKGROUND OF THE INVENTION

In its racemic form, cetirizine, chemically named2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]acetic acid,is an orally active, potent, long acting peripheral histamine H₁receptor antagonist. See, e.g., Juhlin, L., et al. J. Allergy Clin.Immunol. 80:599-602 (1987); De Vos, C., et al. Annal. Allergy 59:278-282(1987); U.S. Pat. No. 4,525,358. Cetirizine is a second generation H₁histamine receptor antagonist that generally offers some significantadvantages beyond the first generation compounds. These advantagesinclude: (1) less sedation, (2) little anticholinergic activity, and (3)longer duration of activity. The medicinal chemistry of cetirizine isdescribed by Campoli-Richards et al., Drugs 40:762-781(1990), Snyder andSnowman, Allergy 59II:4-8 (1987), and Rihoux and DuPont, Annals ofAllergy 59:235-238(1987).

Cetirizine has been employed in the treatment of some symptoms ofallergic reactions. For example, U.S. Pat. No. 5,419,898 to Ikejiri etal. discloses antiallergic compositions containing cetirizine forophthalmic or nasal use. Its efficacy in the treatment of some othersymptoms associated with asthma, however, is limited. Specifically,clinical studies conducted by Gong and coworkers revealed that thecompound, when administered to patients in doses as large as 20 mg, isnot uniformly effective in preventing allergen- or exercise-inducedbronchoconstriction (Gong, H., et al. J. Allergy Clin. Immunol.85:632-641 (1990)).

In only a few cases has cetirizine been combined with other drugs forthe treatment of disease. For example, U.S. Pat. No. 4,829,064 toSunshine et al. discloses compositions useful for treating cold symptomscomprising cetirizine and an analgesic. Published European PatentApplication No. 433766 A1 to York et al. discloses compositions ofcetirizine and an antiallergic compound useful for treating ophthalmicallergic responses.

Although the stereoselectivity of some drugs is well known (see, e.g.,Ariens, E. J. Schweiz. Med. Wocheuschr. 120:131-134 (1994)), disclosuresdirected to the combination of cetirizine with other drugs have taughtaway from combinations comprising optically pure enantiomers ofcetirizine. Recently, however, some advantages of treating certaindiseases with an optically pure enantiomer of cetirizine alone has beenrecognized.

U.S. Pat. No. 5,627,183 discloses methods of treating urticaria usingoptically pure (+) cetirizine. U.S. Pat. No. 5,698,558 discloses methodsof treating certain allergic disorders using (−) cetirizine. Bothpatents disclose that the administration of optically pure enantiomersof cetirizine can reduce or avoid adverse side effects associated withthe use of racemic cetirizine. These side effects include sedation andsomnolence, headache, gastrointestinal disturbance, dizziness, nausea,cardiac arrhythmias, and other cardiovascular effects. Such adverseeffects are common to non-sedating antihistamines.

It has been suggested that the moderate effectiveness of someH₁-antihistamines is due in part to their additional activity againstleukotrienes, particularly leukotriene D₄ (LTD₄). Leukotrienes augmentneutrophil and eosinophil migration, neutrophil and monocyteaggregation, leukocyte adhesion, increase capillary permeability, andsmooth muscle contraction, all of which contribute to inflammation,edema, mucus secretion, and bronchoconstriction.

In one study of guinea pigs, the increase in airway resistance caused byLTD₄ was suppressed by the antihistamine terfenadine. See Akagi et al.,Ovo Yakuri, 35: 361-371 (1988). In another study, twentyH₁-antihistamines with diverse chemical structures were tested foractivity against LTD₄-induced contraction in isolated guinea-pig ileumand displacement of [³H] LTD₄ from guinea-pig lung membrane proteins (M.Zhang et al., Inflamm. res. 46:Supp. I S93-S94 (1997)). The resultsindicated the drugs were weakly active in inhibiting LTD₄-inducedcontraction of guinea pig ileum.

A number of drugs have been designed specifically to inhibit leukotrieneformation. One of these, zileuton, is a specific inhibitor of5-lipoxygenase. Commercially available as ZYFLO®, it has the chemicalname (±)-1-(1-Benso[b]thien-2-ylethyl)-1-hydroxyurea. Zileuton is knownto inhibit leukotriene (LTH₄, LTC₄, LTD₄, and LTE₄) formation in vitro.Zileuton is an inhibitor ex vivo of LTB₄ formation in several speciesand inhibits leukotriene-dependent smooth muscle contractions in vitroin guinea pig and human airways. One study of 373 patients indicatedthat 600 mg of zileuton four times daily were required to provideefficacy, while 400 mg failed to do so. In some patients, zileuton wasreported to cause headache, pain, asthenia, dyspepsia, nausea, andmyalgia (Physician's Desk Reference, 52 ed., Medical Economics Co.,Inc., 474-76 (1998)).

Zafirlukast, sold commercially as ACCOLATE®, is another type ofleukotriene inhibitor. This leukotriene inhibitor is a leukotrienereceptor antagonist (LTRA) of leukotriene D₄ and E₄, and has thechemical name4-(5-cyclopentyloxy-carbonylamino-1-methyl-indol-8-ylmethyl)-3-methoxy-N-o-tolylsulfonylbenzamide.Cysteinyl leukotriene production and receptor occupation have beencorrelated with the pathophysiology of asthma. In vitro studiesindicated that zafirlukast antagonized the contractile activity of threeleukotrienes in conducting airway smooth muscle from laboratory animalsand humans; prevented intradermal LTD₄-induced increases in cutaneousvascular permeability; and inhibited inhaled LTD₄-induced influx ofeosinophils into animal lungs. In some patients, zafirlukast has beenreported to cause headache, infection, nausea, diarrhea, pain, asthenia,abdominal pain, dizziness, myalgia, fever, vomiting, SGPT elevation, anddyspepsia (Physician's Desk Reference, 52 ed., Medical Economics Co.,Inc., 3148-49 (1998)).

3. SUMMARY OF THE INVENTION

The present invention represents an improvement over both the cetirizineand the leukotriene inhibitor technology presently available.

This invention relates to novel pharmaceutical compositions comprising:(a) an optically pure enantiomer of cetirizine, a racemic mixture ofcetirizine, or a pharmaceutically acceptable salt thereof; and (b) aleukotriene inhibitor. These compositions may optionally contain anadditional ingredient, such as a decongestant.

The compositions of the present invention are believed to improve upon,and are superior to, those of the prior art used to treat or preventasthma, asthma symptoms, inflammation, allergic disorders such asallergic rhinitis, and dermatitis. Unexpectedly, it is believed thatthere is a synergistic effect when cetirizine, or an enantiomer or saltthereof, is used in combination with one or more leukotriene inhibitors.Both racemic and optically pure enantiomers of cetirizine may be used toachieve this synergistic effect. Furthermore, the compositions andmethods of this invention avoid or reduce certain adverse side effectsassociated with second generation H₁ histamine receptor antagonists.

The compositions of this invention possess potent antihistaminicactivity. They are useful for treating and preventing the occurrence ofasthma or asthma symptoms. They are also useful for the treatment andprevention of dermatitis, inflammation, and allergic disorders such asallergic rhinitis. The compositions of this invention may also be usedto threat the symptoms of allergic asthma, allergic rhinitis, and otherallergic disorders, as well as dermatitis. In addition, the compositionsof the invention reduce or avoid adverse effects generally associatedwith administration of non-sedating antihistamines, such as racemiccetirizine or an enantiomer of cetirizine. Adverse effects include, butare not limited to, cardiac arrhythmias, drowsiness, nausea, fatigue,weakness and headache.

The compositions of this invention are also useful in combination withnon-steroidal anti-inflammatory agents or other non-narcotic analgesicsfor the treatment or prevention of inflammation, cough, cold, cold-like,and/or flu symptoms and the discomfort, headache, pain, fever, andgeneral malaise associated therewith. The aforementioned combinations(e.g., an enantiomer or racemic mixture of cetirizine and a leukotrieneinhibitor) may optionally include one or more other active componentsincluding a decongestant, cough suppressant/antitussive, or expectorant.

Additionally, the novel pharmaceutical compositions of the invention areuseful in treating, preventing, or managing motion sickness, vertigo,diabetic retinopathy, small vessel complications due to diabetes andsuch other conditions as may be related to the activity of thesederivatives as antagonists of the H₁ histamine receptor. Thecompositions can be used to treat or prevent these disorders whilereducing or avoiding adverse effects associated with administration ofnon-sedating antihistamines.

In one embodiment, this invention provides for a method of treating orpreventing asthma or asthma symptoms in a human which comprisesadministering to a human a therapeutically effective amount of anoptically pure enantiomer of cetirizine, racemic cetirizine, or apharmaceutically acceptable salt thereof, and a therapeuticallyeffective amount of a leukotriene inhibitor, or a pharmaceuticallyacceptable salt thereof. Preferably, the leukotriene inhibitor is a5-lipoxygenase inhibitor or a 5-lipoxygenase activating proteinantagonist.

The invention also provides a method of treating or preventing asthma orasthma symptoms in a human comprising administering to a human acomposition, said composition comprising (i) a therapeutically effectiveamount of an optically pure enantiomer of cetirizine, racemiccetirizine, or a pharmaceutically acceptable salt thereof; (ii) aleukotriene inhibitor, or a pharmaceutically acceptable salt thereof,selected from the group consisting of 5-lipoxygenase inhibitors,5-lipoxygenase activating protein antagonists, and leukotriene receptorantagonists; and a pharmaceutically acceptable carrier or excipient.

This invention is further directed to a method of treating or preventingasthma or the symptoms of asthma in a human which comprisesadministering to a human therapeutically effective amounts of anoptically pure enantiomer of cetirizine, racemic cetirizine, or apharmaceutically acceptable salt thereof, a leukotriene inhibitor, or apharmaceutically acceptable salt thereof, and a decongestant.Preferably, the leukotriene inhibitor is a 5-lipoxygenase inhibitor or a5-lipoxygenase activating protein antagonist.

In a second embodiment, the invention provides for a method of treatingor preventing dermatitis in a human which comprises administering to ahuman a therapeutically effective amount of an optically pure enantiomerof cetirizine, racemic cetirizine, or a pharmaceutically acceptable saltthereof, and a leukotriene inhibitor, or a pharmaceutically acceptablesalt thereof.

In a third embodiment, the invention provides for a method of treatingor preventing allergic rhinitis in a human which comprises administeringto a human a therapeutically effective amount of an optically pureenantiomer of cetirizine, racemic cetirizine, or a pharmaceuticallyacceptable salt thereof, and a leukotriene inhibitor, or apharmaceutically acceptable salt thereof. Preferably, the leukotrieneinhibitor is a 5-lipoxygenase inhibitor or a 5-lipoxygenase activatingprotein antagonist.

In a fourth embodiment, the invention provides for a method of treatingor preventing inflammation in a human which comprises administering to ahuman a therapeutically effective amount of an optically pure enantiomerof cetirizine, racemic cetirizine, or a pharmaceutically acceptable saltthereof, and a leukotriene inhibitor, or a pharmaceutically acceptablesalt thereof.

In a fifth embodiment, the invention provides for a method of preventingor treating a condition responsive to leukotriene inhibition whichcomprises administering to a human a therapeutically effective amount ofcetirizine, or a pharmaceutically acceptable salt thereof, a leukotrieneinhibitor, or a pharmaceutically acceptable salt thereof, and optionallya decongestant, or a pharmaceutically acceptable salt thereof.

The invention encompasses the treatment, prevention, and/or managementof these disorders using a single unit dosage form that contains anoptically pure enantiomer of cetirizine or racemic cetirizine, or apharmaceutically acceptable salt thereof, and a leukotriene inhibitor,or a pharmaceutically acceptable salt thereof, such that the cetirizinecomponent and leukotriene inhibitor are in one solid or liquid dosageform. It should be recognized, however, that combination therapy byseparate administration of each active ingredient is also contemplated.

Consequently, the administration of the active ingredients (i.e.,optically pure or racemic cetirizine and leukotriene inhibitor, andoptionally decongestant) of this invention may be concurrent orsequential. For example, a cetirizine component and a leukotrieneinhibitor may be administered as a combination, concurrently butseparately, or by the sequential administration of cetirizine andleukotriene inhibitor or the sequential administration of a leukotrieneinhibitor and cetirizine. Cetirizine may be administered in a similarmanner with a decongestant.

4. DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses the treatment, prevention, and/ormanagement of asthma, the symptoms of asthma, dermatitis, inflammation,or allergic disorders, such as allergic rhinitis, using an opticallypure enantiomer of cetirizine or racemic cetirizine, or apharmaceutically acceptable salt thereof, in combination with aleukotriene inhibitor; and optionally a decongestant.

According to the present invention, all means of treatment, prevention,and/or management of these disorders, including, but not limited to,topical, local, and systemic, may employ racemic cetirizine, opticallypure (+) cetirizine or (−) cetirizine, or a pharmaceutically acceptablesalt thereof. It is preferred, however, that (+) cetirizine, or apharmaceutically acceptable salt thereof, in combination with aleukotriene inhibitor, and optionally a decongestant, be used for thetopical or local treatment, prevention, and/or management of dermatitis,inflammation, or related disorders. It is preferred that (−) cetirizine,or a pharmaceutically acceptable salt thereof, be used in combinationwith a leukotriene inhibitor, and optionally a decongestant, for thesystemic treatment of asthma, the symptoms of asthma, or allergicdisorders, such as allergic rhinitis.

Without being limited by theory, it is believed that (−) cetirizinegenerally has a lower affinity towards the cortex H₁histamine receptorthan (+) cetirizine. Consequently, the administration of (−) cetirizinein combination with a leukotriene inhibitor and optionally adecongestant may have fewer undesirable effects on the central nervoussystem, such as sedation or drowsiness, than would result fromadministration of the corresponding (+) cetirizine combination. At thesame time, (+) cetirizine is able to inhibit the effects of histaminepresent in high local concentrations. For at least this reason, topicalor local treatment, prevention, and/or management of inflammation andother disorders may be more effective with the administration of (+)cetirizine in combination with a leukotriene inhibitor and optionally adecongestant than with the administration of the corresponding (−)cetirizine combination.

It should be recognized that the invention includes the use of thecetirizine active ingredient and the leukotriene inhibitor as acombination either in a single composition, or separately butconcurrently and/or sequentially. The same is true when an optionaldecongestant is used.

The methods and compositions of this invention are believed to reduce oravoid adverse effects associated with administration of non-sedatingantihistamines, and particularly with administration of racemiccetirizine alone. The methods and compositions described herein arebelieved to provide superior or improved therapy over prior art methodsand compositions involving optically pure or racemic cetirizine in theabsence of a leukotriene inhibitor, or a leukotriene inhibitor in theabsence of optically pure or racemic cetirizine. Without being limitedby theory, it is believed that the combination of optically pure orracemic cetirizine, or a pharmaceutically acceptable salt thereof, aleukotriene inhibitor, or a pharmaceutically acceptable salt thereof,and optionally a decongestant, provides superior, improved, andsynergistic effects unachievable by any of these compounds alone.

The preparation of racemic cetirizine can be performed by the methodsdescribed in U.S. Pat. No. 2,899,436 to Morren et al., U.S. Pat. No.4,525,358 to Bates et al., or by an improved procedure described inBritish Application No. 2,225,320 of Cossement et al., the disclosuresof which are hereby expressly incorporated herein by reference theretofor this purpose. Synthesis of substantially optically pure (+) and (−)enantiomers of cetirizine is described in British Application No.2,225,320 of Cossement et al., as well as in U.S. Pat. No. 5,478,941 toCossement et al., the disclosures of which are also expresslyincorporated herein by reference thereto. Alternatively, the opticallypure enantiomers can be resolved from the racemic mixture using standardtechniques available in the art.

As used herein, the terms “adverse effects” and “adverse side effects”include, but are not limited to, cardiac arrhythmias, cardiac conductiondisturbances, appetite stimulation, weight gain, sedation,gastrointestinal distress, headache, dry mouth, constipation, anddiarrhea. The term “cardiac arrhythmias” includes, but is not limitedto, ventricular tachyarrhythmias, torsades de pointes, and ventricularfibrillation.

The term “asthma” as used herein is defined as a disorder characterizedby increased responsiveness of the trachea and bronchi to variousstimuli, which results in symptoms that include, but are not limited to,wheezing, cough, shortness of breath, dyspnea, and the like. Asthmaincludes, for example, allergic asthma.

The term “dermatitis” as used herein is that disorder caused byinflammation to the skin including endogenous and contact dermatitissuch as, but not limited to: actinic dermatitis (or photodermatitis),atopic dermatitis, chemical dermatitis, cosmetic dermatitis, dermatitisaestivalis, and seborrheic dermatitis.

As used herein, the term “pharmaceutically acceptable salt” refers to asalt prepared from pharmaceutically acceptable non-toxic acids or basesincluding inorganic acids or bases or organic acids or bases. Examplesof such inorganic acids are hydrochloric, hydrobromic, hydroiodic,sulfuric, and phosphoric. Appropriate organic acids may be selected, forexample, from aliphatic, aromatic, carboxylic and sulfonic classes oforganic acids, examples of which are formic, acetic, propionic,succinic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic,anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic, stearic,sulfanilic, algenic, and galacturonic. Examples of such inorganic basesinclude metallic salts made from aluminum, calcium, lithium, magnesium,potassium, sodium, and zinc. Appropriate organic bases may be selected,for example, from N,N-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysineand procaine.

The terms “substantially optically pure,” “optically pure,” and“optically pure enantiomers” as used herein mean that the compositioncontains greater than about 95% of the desired enantiomer by weight,preferably greater than about 98% of the desired enantiomer by weight,and most preferably greater than about 99% of the desired enantiomer byweight, said percent based upon the total weight of cetirizine. In otherwords, the term “substantially free” means less than about 5 weightpercent, preferably less than about 2 weight percent, and morepreferably less than about 1 weight percent.

The term “cetirizine” when used without modification means the compoundin all its forms, including, but not limited to, racemic cetirizine,optically pure enantiomers of cetirizine, and mixtures thereof.

The term “racemic” as used herein means a mixture of the (+) and (−)enantiomers of a compound wherein the (+) and (−) enantiomers arepresent in approximately a 1:1 ratio.

The phrase “therapeutically effective amount of cetirizine” as usedherein means that amount of optically pure or racemic cetirizine, or apharmaceutically acceptable salt thereof, which, alone or in combinationwith other drugs, provides a therapeutic benefit in the treatment,management, or prevention of conditions that are responsive to histamineantagonists, such as asthma, asthma symptoms, allergic disorders such asallergic rhinitis, and dermatitis.

The phrase “therapeutically effective amount of leukotriene inhibitor”as used herein means that amount of leukotriene inhibitor which alone,or in combination with other drugs, provides a therapeutic benefit inthe treatment, management, or prevention of any condition that isresponsive to leukotriene inhibitors, such as asthma, asthma symptoms,inflammation, allergic disorders such as allergic rhinitis, anddermatitis.

The phrase “therapeutically effective amount of a decongestant” as usedherein means that amount of decongestant which alone, or in combinationwith other drugs, provides a therapeutic benefit in the treatment,management, or prevention of congestion of the respiratory tract and/orsinus.

The term “leukotriene inhibitor” as used herein includes any agent orcompound that inhibits, restrains, retards or otherwise interacts withthe action or activity of leukotrienes, such as, but not limited to,5-lipoxygenase (“5-LO”) inhibitors, 5-lipoxygenase activating protein(“FLAP”) antagonists, and leukotriene receptor antagonists (“LTRAs”).

The term “5-lipoxygenase inhibitor” or “5-LO inhibitor” as used hereinincludes any agent or compound that inhibits, restrains, retards orotherwise interacts with the enzymatic action of 5-lipoxygenase, suchas, but not limited to, zileuton, docebenone, piripost, and ICI-D2318.

The term “5-lipoxygenase activating protein antagonist” or “FLAPantagonist” as used herein includes any agent or compound that inhibits,restrains, retards or otherwise interacts with the action or activity of5-lipoxygenase activating protein, such as, but not limited to, MK-591and MK-886.

The term “leukotriene receptor antagonist” or “LTRA” as used hereinincludes any agent or compound that inhibits, restrains, retards orotherwise antagonizes the activity of receptors that are responsive toleukotrienes, including those responsive to leukotriene D₄. ExemplaryLTRAs include sodium1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)-ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methyl)-cyclopropaneacetate,1-(((1(R)-(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneaceticacid or salts thereof, pranlukast, zafirlukast (ICI-204219), andmontelukast (MK-476), the latter of which is sold commercially asSINGULAIR®.

The magnitude of a prophylactic or therapeutic dose of optically pure orracemic cetirizine or leukotriene inhibitor in the acute or chronicprevention, treatment, or management of a disorder or condition willvary with the severity of the condition to be treated and the route ofadministration. The dose, and perhaps the dose frequency, will also varyaccording to the age, body weight, and response of the individualpatient. The magnitude of the dose may also depend upon whetheroptically pure or racemic cetirizine is used. Furthermore, if anoptically pure enantiomer of cetirizine is used, the magnitude of thedose may depend upon whether it is the (+) or (−) enantiomer. Suitabletotal daily dose ranges can be readily determined by those skilled inthe art. In general, the total daily dose range for optically pure orracemic cetirizine, for the conditions described herein, is from about0.01 mg to about 50 mg administered in single or divided doses. Forexample, a preferred oral daily dose range should be from about 1 mg toabout 30 mg. A more preferred oral dose is about 5 mg to about 25 mg. Apreferred oral daily dose range of decongestant, such aspseudoephedrine, should be from about 50 mg to about 300 mg, morepreferably, about 150 mg to about 250 mg. In addition, suitable oraldaily dosage ranges of leukotriene inhibitor can be readily determinedby those skilled in the art (see, e.g., Physician's Desk Reference). Forexample, for 5-lipoxygenase inhibitors, a preferred oral daily doserange of leukotriene inhibitor should typically be from about 20 mg to2,500 mg, preferably about 20 mg to 800 mg. For leukotriene receptorantagonists, a preferred oral daily dose of leukotriene inhibitor shouldtypically be from about 2 mg to 100 mg, preferably about 5 mg to 20 mg.

It is further recommended that children, patients aged over 65 years,and those with impaired renal or hepatic function initially receive lowdoses, and that they then be titrated based on individual response(s) orblood level(s). It may be necessary to use dosages outside these rangesin some cases as will be apparent to those skilled in the art. Further,it is noted that the clinician or treating physician will know how andwhen to adjust, interrupt, or terminate therapy in conjunction withindividual patient response.

Any suitable route of administration may be employed for providing thepatient with an effective dosage of an optically pure or racemiccetirizine and leukotriene inhibitor according to the methods of thepresent invention. For example, oral, intraoral, rectal, parenteral,epicutaneous, transdermal, subcutaneous, intramuscular, intranasal,sublingual, buccal, intradural, intraocular, intrarespiratory, or nasalinhalation and like forms of administration may be employed. Oraladministration is generally preferred. For the methods to treatdermatitis, however, topical administration is preferred.

The pharmaceutical compositions used in the methods of the presentinvention, which are sterile and stable, include optically pure orracemic cetirizine, or a pharmaceutically acceptable salt thereof, aleukotriene inhibitor, or a pharmaceutically acceptable salt thereof,and optionally a decongestant, as the active ingredient. Thecompositions may also contain a pharmaceutically acceptable carrier orexcipient, and, optionally, other therapeutic ingredients.

The compositions for use in the methods of the present invention caninclude suitable excipients or carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like.

Dosage forms include tablets, troches, dispersions, suspensions,solutions, capsules, patches, gel caps, syrups, elixirs, gels, powders,magmas, lozenges, ointments, creams, pastes, plasters, lotions, discs,suppositories, nasal or oral sprays, aerosols, and the like.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit fort, in which case solidpharmaceutical carriers are employed. If desired, tablets may be coatedby standard aqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compound foruse in the methods of the present invention may also be administered bycontrolled release means and/or delivery devices such as those describedin U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and4,008,719, the disclosures of which are expressly incorporated herein byreference thereto.

Pharmaceutical compositions for use in the methods of the presentinvention may be prepared by any of the methods of pharmacy, but allmethods include the step of bringing into association the activeingredient with the carrier which constitutes one or more necessaryingredients. In general, the compositions are prepared by uniformly andintimately admixing the active ingredient with liquid carriers or finelydivided solid carriers or both, and then, if necessary, shaping theproduct into the desired presentation.

For example, a tablet may be prepared by compression or molding,optionally, with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as powder or granules, optionallymixed with a binder, lubricant, inert diluent, surface active ordispersing agent. Molded tablets may be made by molding, in a suitablemachine, a mixture of the powdered compound moistened with an inertliquid diluent.

The invention is further defined by reference to the following examplesdescribing in detail the preparation of the composition and thecompositions used in the methods of the present invention, as well astheir utility. It will be apparent to those skilled in the art that manymodifications, both to materials and methods, may be practiced which arewithin the scope of this invention.

5. EXAMPLES

5.1 Synthesis of Racemic Cetirizine:

The dihydrochloride salt of(±)2-[2-[-4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-aceticacid may be prepared according to the method of Cossement et al.,disclosed in British Patent Application No. 2,225,321.

In 250 ml of ethanol, 23 g (0.062 mole) of racemic2-[2-[-4-[(4-chlorophenylmethyl]-1-piperazinyl]ethoxy]-acetonitrile and31 ml of a 4N ethanolic solution of potassium hydroxide are introducedsuccessively into a three-necked round-bottomed flask equipped with amechanical stirrer, a condenser and a thermometer. The reaction mixtureis refluxed for 10 hours, while stirring. It is then allowed to cool andits pH is brought to 6 by addition of 37% concentrated hydrochloricacid. The ethanol is evaporated and the reaction mixture is diluted with100 ml of water and extracted three times with 200 ml ofdichloromethane.

The organic phases are combined, dried over magnesium sulphate,filtered, and concentrated in a rotary evaporator. An oil is obtainedand is allowed to crystallize by addition of 100 ml of 2-butanone, whilehot. The solid formed is filtered, washed, and dried to obtain 18.9 g ofracemic2-[2-[-4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-aceticacid.

The acid is resuspended in 150 ml of water, the pH of which is broughtto 0.8 by addition of concentrated hydrochloric acid. The aqueoussolution is concentrated on a rotary evaporator and the residue is thendiluted by addition of 75 ml of 2-butanone. This induces crystallizationof racemic2-[2-[-4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-aceticacid dihydrochloride. The crystals are filtered off and dried to yield21.7 g (75.9%) of product. The melting point of the crystals is 220.15°C. as measured by differential scanning calorimetry (DSC).

5.2 Alternative Synthesis of Racemic Cetirizine:

Alternatively,(±)2-[2-[-4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]-aceticacid may be prepared according to the method of Baltes et al. disclosedin U.S. Pat. No. 4,525,358. In this method,2-[2-[4-Diphenylmethyl)-1-piperazinyl]ethoxy]-acetamide dihydrochlorideis first synthesized as follows.

A mixture of 37.8 g (0.15 mole) of 1-(diphenylmethyl)-piperazine, 27.5 g(0.2 mole of 2-(2-chloroethoxy)-acetamide and 26.5 g of anhydrous sodiumcarbonate in 120 ml of xylene is heated for 4 hours to 90° C. to 120° C.Thereafter, 120 ml of benzene are added to the reaction mixture, theprecipitate formed is filtered off and the organic phase is extractedwith dilute hydrochloric acid (30 ml of concentrated hydrochloric acidand 100 ml of water). 40 ml of a concentrated aqueous solution of sodiumhydroxide are added, followed by extraction with benzene. The benzenesolution is washed with water, dried over anhydrous sodium carbonate andthe benzene is evaporated off to dryness. The evaporation residue istitrated with diethyl ether and left to crystallize.2-[2-[4-Diphenylmethyl)-1-piperazinyl]ethoxy]-acetamide is obtained in ayield of 73% (M.P. 119° C.-120° C.).

In the second part of the synthesis, a mixture of 19 g (0.054 mole) of2-[2-[4-diphenylmethyl)-1-piperazinyl]ethoxy[-acetamide in 200 ml ofethanol and 27 ml of a 4 N ethanolic solution of sodium hydroxide isheated under reflux for 3 hours. The reaction mixture is adjusted with29.7 ml of 3.61 N hydrochloric acid to a pH of 6.3, whereafter theethanol is evaporated off in a vacuum. The precipitate obtained isfiltered off. After evaporation of the solvent, 17.4 g of crude2-[2-[4-diphenylmethyl)-1-piperazinyl]ethoxy]-acetic acid are obtained(yield=91%; M.P. 100° C.). This product may be purified by conventionalmeans known to those skilled in the art.

5.3 Synthesis of Optically Pure (+) Cetirizine:

The dihydrochloride salt of(+)2-[2-[-4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-aceticacid may be prepared according to the method of Cossement et al.disclosed in British Patent Application No. 2,225,321.

9.42 g (0.0255 mole) of levorotatory2-[2-[4-[(4-chlorophenyl)phenylmethyl)-1-piperazinyl]ethoxy]-acetonitrileare introduced into a reactor equipped with a mechanical stirrer, acondenser, a thermometer, and a dropping funnel and are heated to 45°C., while stirring. 15 ml of 37% concentrated hydrochloric acid are thenadded. The temperature of the reaction mixture rises to 92° C. Thetemperature of the reaction mixture is maintained at 60° C. for 60minutes while stirring. The reaction mixture is allowed to cool and isconcentrated on a rotary evaporator. The residue is then taken up in 50ml of water. The pH of the reaction mixture is brought to 5 by additionof sodium hydroxide and the mixture is extracted with several successivefractions of dichloromethane. The organic phases are combined and driedover magnesium sulphate and the solvent is removed on a rotaryevaporator. 9.6 g of the free acid of the final product are thusobtained in the form of a beige powder, which are then converted intothe dihydrochloride by means of a solution of hydrochloric acid inacetone. The dihydrochloride is crystallized from this solution. Afterfiltration and drying, 9.8 g of(+)2-[2-(4-[(4-chlorophenyl)phenylmethyl)-1-piperazinyl]ethoxy]-aceticacid dihydrochloride are obtained. The purity of this product, obtainedin 83% yield, may be measured by high performance liquid chromatographywith a chiral stationary phase of a α₁-AGP (from the LKB Company). It istypically 95% with respect to the dextrorotatory enantiomer. The producthas a melting point of 199-201° C. (224.4° C. as measured by DSC), andan [α] of +9.4° (c=1, water).

5.4 Synthesis of Optically Pure (−) Cetirizine:

This product is obtained by the method described in example 5.3, butstarting from dextrorotatory1-[(4-chlorophenyl)phenylmethyl)-piperazine, the latter being obtainedby treating the racemate with (2S,3S)-tartaric acid using techniquesknown to those skilled in the art.

The dihydrochloride salt of(−)2-[2-[-4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-aceticacid is obtained in yields and with a purity very close to thoseobtained for the dextrorotatory acid dihydrochloride: 95% measured byhigh performance liquid chromatography with a chiral stationary phase ofα₁-AGP (from the LKB Company). The product has a melting point of198-200° C. (220.7° C. as measured by DSC), but decomposes upon melting.

While the present invention has been described with respect to theparticular embodiments, it will be apparent to those skilled in the artthat various changes and modifications may be made without departingfrom the spirit and scope of the invention as defined in the claims.Such modifications are also intended to fall within the scope of theappended claims.

1-7. (Canceled without prejudice)
 8. A method of preventing dermatitisin a human which comprises administering to a human a pharmaceuticalcomposition consisting essentially of a therapeutically effective amountof optically pure (−) cetirizine or a pharmaceutically acceptable saltthereof, and a therapeutically effective amount of a leukotrieneinhibitor, or a pharmaceutically acceptable salt thereof.
 9. The methodof claim 8, wherein the leukotriene inhibitor is a 5-lipoxygenaseinhibitor, a 5-lipoxygenase activating protein antagonist, a leukotrienereceptor antagonist, or a mixtures thereof. 10-13. (Canceled withoutprejudice)
 14. A method of preventing allergic rhinitis in a human whichcomprises administering to a human a pharmaceutical compositionconsisting essentially of a therapeutically effective amount ofoptically pure (−) cetirizine or a pharmaceutically acceptable saltthereof, and a therapeutically effective amount of a leukotrieneinhibitor, or a pharmaceutically acceptable salt thereof.
 15. The methodof claim 14, wherein the leukotriene inhibitor is a 5-lipoxygenaseinhibitor, a 5-lipoxygenase activating protein antagonist, a leukotrienereceptor antagonists, or a mixtures thereof. 16-19. (Canceled withoutprejudice)
 20. A method of preventing inflammation in a human whichcomprises administering to a human a pharmaceutical compositionconsisting essentially of a therapeutically effective amount ofoptically pure (−) cetirizine or a pharmaceutically acceptable saltthereof, and a therapeutically effective amount of a leukotrieneinhibitor, or a pharmaceutically acceptable salt thereof.
 21. The methodof claim 20, wherein the leukotriene inhibitor is a 5-lipoxygenaseinhibitor, a 5-lipoxygenase activating protein antagonist, a leukotrienereceptor antagonist, or a mixture thereof. 22-25. (Canceled withoutprejudice)
 26. A method of preventing a condition responsive toleukotriene inhibition which comprises administering to a human apharmaceutical composition consisting essentially of a therapeuticallyeffective amount of optically pure (−) cetirizine or a pharmaceuticallyacceptable salt thereof, and a therapeutically effective amount of aleukotriene inhibitor, or a pharmaceutically acceptable salt thereof.27. The method of claim 26, wherein the leukotriene inhibitor is a5-lipoxygenase inhibitor, a 5-lipoxygenase activating proteinantagonist, a leukotriene receptor antagonist, or a mixture thereof.28-31. (Canceled without prejudice)
 32. The method of claim 26 whereinthe condition responsive to leukotriene inhibition comprises asthma or asymptom thereof.
 33. The method of claim 26 wherein the conditionresponsive to leukotriene inhibition comprises an allergic condition.34. The method of claim 26 wherein the condition responsive toleukotriene inhibition comprises inflammation. 35-44. (Canceled withoutprejudice)
 45. A pharmaceutical composition which comprises: (a) atherapeutically effective amount of optically pure (−) cetirizine, or apharmaceutically acceptable salt thereof; (b) a therapeuticallyeffective amount of a leukotriene inhibitor, or a pharmaceuticallyacceptable salt thereof, wherein the leukotriene inhibitor is a5-lipoxygenase inhibitor, a 5-lipoxygenase activating proteinantagonist, and a leukotriene receptor antagonist, and or a mixturethereof, and (c) a pharmaceutically acceptable carrier or excipient. 46.A pharmaceutical composition which comprises from about 0.1 mg to 50 mgof optically pure (−) cetirizine, or a pharmaceutically acceptable saltthereof, and from about 2 mg to about 100 mg of leukotriene receptorantagonist, or a pharmaceutically acceptable salt thereof.
 47. Apharmaceutical composition which comprises from about 0.1 mg to 50 mg ofoptically pure (−) cetirizine, or a pharmaceutically acceptable saltthereof, and from about 20 mg to about 2500 mg of 5-lipoxygenaseinhibitor, or a pharmaceutically acceptable salt thereof.
 48. Apharmaceutical composition which comprises from about 0.1 mg to 50 mg ofoptically pure (−) cetirizine, or a pharmaceutically acceptable saltthereof, and from about 20 mg to about 2500 mg of 5-lipoxygenaseactivating protein antagonist, or a pharmaceutically acceptable saltthereof.
 49. The pharmaceutical composition of claim 45 which furthercomprises a therapeutically effective amount of a decongestant, or apharmaceutically acceptable salt thereof. 50-52. (Canceled withoutprejudice)